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Tumor-Specific Antigens High-Avidity T Cell Responses to CD 8 T Cells Induces Protective and TNF Receptor Family-Related Receptor on Stimulation of the Glucocorticoid-Induced
| Content Provider | Semantic Scholar |
|---|---|
| Author | Zhang, Peisheng Sullivan, Jeremy A. O’ Jacobs, Valerie L. Clemis, Carli R. Sakaguchi, Shimon Guevara-Patino, Jose Turk, Mary Jo |
| Copyright Year | 2010 |
| Abstract | Treatment of tumor-bearing mice with a stimulatory Ab to glucocorticoid-induced TNFR family-related receptor (GITR) has previously been shown to elicit protective T cell responses against poorly immunogenic tumors. However, the role of GITR stimulation on CD8 T cells and the nature of tumor rejection Ags have yet to be determined. In this study, we show that a stimulatory mAb to GITR (clone DTA-1) acts directly on CD8 T cells, but not on CD4 + CD25 + regulatory T (T reg) cells, in B16 tumor-bearing mice to induce concomitant immunity against secondary B16 tumors, as well as protective memory following surgical excision of the primary tumor. Melanoma growth itself induced GITR expression on tumor-specific CD8 T cells, providing a mechanism whereby these cells may respond to stimulatory anti-GITR. Unexpectedly, in contrast to T reg cell depletion therapy with anti-CD4, GITR stimulation induced very weak CD8 T cell responses to melanocyte differentiation Ags expressed by the tumor, and did not induce autoimmune vitiligo. Accordingly, GITR-stimulated hosts that were primed with B16 melanoma rejected B16, but not the unrelated JBRH melanoma, indicating that tumor rejection Ags are tumor-specific rather than shared. In support of this, we show that GITR stimulation induces CD8 T cell responses to a tumor-specific Ag, and that these responses are of higher functional avidity compared with those induced by T reg cell depletion. We conclude that stimulation of GITR on effector CD8 T cells results in high-avidity T cell responses to tumor-specific Ags, thereby inducing potent antitumor immunity in the absence of auto-immunity. A major challenge of cancer immunotherapy has been the generation of antitumor immunity in the absence of au-toimmunity. In addition to self-Ags, tumors express unique Ags that are derived from mutated proteins (1–3) and can serve as potent tumor-rejection Ags (4–6). Therapies that stimulate immunity against such tumor-specific Ags, rather than self-Ags, may provide more potent and durable antitumor immunity without eliciting autoimmunity (3, 6, 7). However, autoim-munity has been unavoidable when T cell responses are globally and nonspecifically induced by therapies such as CTLA-4 blockade and regulatory T (T reg) cell depletion (8–10). The glucocorticoid-induced TNFR family-related receptor (GITR) is a member of the costimulatory TNFR subfamily that is consti-tutively expressed on T reg cells and upregulated by CD8 and CD4 effector T cells upon activation (11, 12). Treatment with agonistic anti-GITR (clone DTA-1) has been shown to induce rejection of highly immunogenic tumors (4, … |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.jimmunol.org/content/jimmunol/early/2010/11/23/jimmunol.1001308.full.pdf?with-ds=yes |
| Alternate Webpage(s) | http://www.jimmunol.org/content/jimmunol/186/1/275.full.pdf?with-ds=yes |
| Alternate Webpage(s) | http://www.jimmunol.org/content/jimmunol/early/2010/11/23/jimmunol.1001308.full.pdf |
| Alternate Webpage(s) | http://www.dartmouth.edu/~turklab/Papers/Cote%20et%20al.,%20J%20Immunol,%202011.pdf |
| Alternate Webpage(s) | http://www.jimmunol.org/content/jimmunol/186/1/275.full.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
